Combi-Chem

3g. Combinatorial design

Diverse combinatorial design

If you have just finished the previous section of this tutorial, start a new session by selecting File/New Session from the Visualizer menu bar. Click Confirm in the Re-initialize All message window. You may also start from a brand new Cerius2 session.

2.   Open an empty study table

Go to the LIBRARY ANALYSIS card located in the COMBI-CHEM I deck and select the Show Study Table item.

3.   Recall a library of substituted aromatic compounds

Open the Open Study Table control panel by selecting the File/Open... item from the menu bar in the Study Table control panel. Select the table ./Cerius2-Resources/COMBICHEM/demos/phenylR1R2R3_pca.tbl and click the OPEN pushbutton.

Note

4.   Plot the samples in PCA space

Click the 3D Plot tool on the toolbar in the Study Table control panel. Set X, Y, and Z to PC1, PC2, and PC3, respectively. Set the Label Row by popup to Star. Do not change the other defaults in the 3D Plot Samples control panel. Click the 3D Plot pushbutton.

The 3D graph appears in the Cerius² Models window.

5.   Define combinatorial selection conditions

Go to the LIBRARY ANALYSIS card located in the COMBI-CHEM I deck and select the Rgroup Subsetting/Diverse Library item to open the Rgroup subsetting: Diverse Library control panel. Set Number of fragments to select in each Rgroup to 3,4,3 and change Diversity Metric to Max MinSpanTree.

These settings specify that you select 3 substituents for R1, 4 for R2, and 3 for R3. The Max MinSpan Tree metric will be used for the optimization of molecular diversity.

Click the Preferences... pushbutton in the Rgroup subsetting: Diverse Library control panel to open the Analysis Preferences control panel. Check the Show Tree in 3D Plot check box in the Analysis Preferences control panel. Leave the other controls unchanged from their current defaults and close the Analysis Preferences control panel.

6.   Perform the combinatorial selection

Click the SELECT RGROUP FRAGMENTS pushbutton in the Rgroup subsetting: Diverse Library control panel.

The selected R groups are first listed in the text window. The models corresponding to this array design are then reported and also appear as selected rows in the study table.

A representation of the spanning tree also appears in the Cerius² Models window. To superimpose this representation on the PCA plot, use the Overlay mode tool in the Model Manager.

Focused combinatorial design

If you have just finished the previous section of this tutorial, start a new session by selecting File/New Session from the Visualizer menu bar. Click Confirm in the Re-initialize All message window. You can also start from a brand new Cerius2 session.

2.   Open an empty study table

Go to the LIBRARY ANALYSIS card located in the COMBI-CHEM I deck and select the Show Study Table item.

3.   Recall a library of dipeptides

Open the Open Study Table control panel by selecting the File/Open... item from the menu bar in the Study Table control panel. Select the table ./Cerius2-Resources/COMBICHEM/demos/dipep_400_pca.tbl and click the OPEN pushbutton.

Note

4.   Plot the samples in PCA space

Click the 3D Plot tool on the toolbar in the Study Table control panel. Set X, Y, and Z to PC1, PC2, and PC3, respectively. Set the Label Row by popup to Star. Set the Normalize columns popup to None. Do not change the other defaults in the 3D Plot Samples control panel. Then click the 3D Plot pushbutton.

The 3D graph appears in the Cerius² Models window.

5.   Recall the target structure for focusing

Go to the Visualizer main control panel and select the File/Load Model... menu item to open the Load Model control panel. Select the file ./Cerius2-Resources/COMBICHEM/demos/dipep.msi and click the LOAD pushbutton to load the target dipeptide structure.

Now make dipep the selected model by clicking on the corresponding model ID on the left of the diamond shaped icon in the visualizer panel.

6.   Library focusing

The following library focusing example illustrates how a virtual combinatorial may be focused around the given target compound.

Go to the LIBRARY ANALYSIS card in the COMBI-CHEM I deck and select the Rgroup Subsetting/Focused Library item to open the Rgroup subsetting: Focused Library control panel. Set Number of fragments to select in each Rgroup to 4,6.

These settings specify an array of 24 compounds (4 substituents for R1 and 6 for R2) for focusing around the target model.

Click the SELECT RGROUP FRAGMENTS pushbutton in the Rgroup subsetting: Focused Library control panel.

The selected R groups are first listed in the text window. The models corresponding to this array design are then reported and also appear as selected rows in the study table.

7.   Interpretation of the results

A representation of the focusing experiment appears in the Cerius² Models window. The compound in grey is the target compound for focusing. The compounds in red are the 24 combinatorially selected compounds from the dipeptide library. You can see that they are indeed in the vicinity of the target compound. The compounds in green are the remaining compounds from the dipeptide library.